Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss.
Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss.
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DOI：
10.1021/acs.jmedchem.8b00669
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发表时间：
2018-09-13
影响因子：
7.3
通讯作者：
Zuo J
中科院分区：
文献类型：
--
作者：
Hazlitt RA;Teitz T;Bonga JD;Fang J;Diao S;Iconaru L;Yang L;Goktug AN;Currier DG;Chen T;Rankovic Z;Min J;Zuo J
目前尚无 FDA 批准的疗法可以预防与化疗方案中使用顺铂相关的听力损失。我们最近证明，用 kenpaullone 进行药理抑制或 CDK2 基因缺失可以在顺铂治疗的动物模型中保留听力功能，这表明 CDK2 是预防顺铂引起的耳毒性的有前途的治疗靶点。在这项研究中，我们从 187 种 CDK2 抑制剂的集中库筛选中鉴定出两种先导化合物 AT7519 和 AZD5438，这些筛选是在来自用顺铂处理的新生小鼠耳蜗的永生化细胞系中进行的。此外，我们筛选了 36 个 AT7519 类似物，并鉴定了类似物 7，其表现出改善的治疗指数。当局部递送时，类似物 7 和 AZD5438 均针对顺铂诱导的小鼠耳毒性提供了显着的保护作用。因此，我们已经鉴定出另外两种可在体内预防顺铂诱导的耳毒性的化合物，并提供进一步的证据表明CDK2是治疗顺铂诱导的耳毒性的药物靶点。
There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compounds, AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogs of AT7519 and identified analog 7, which exhibited an improved therapeutic index. When delivered locally, analog 7 and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two additional compounds that prevent cisplatin-induced ototoxicity in vivo, and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.
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影响因子：
6
作者：
Ciarimboli, Giuliano;Deuster, Dirk;Schlatter, Eberhard
通讯作者：
Schlatter, Eberhard
影响因子：
2.8
作者：
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通讯作者：
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影响因子：
3.9
作者：
Sooriyaarachchi, Melani;Gailer, Jurgen;George, Graham N.
通讯作者：
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影响因子：
7.3
作者：
Wyatt, Paul G.;Woodhead, Andrew J.;Woolford, Alison J. -A.
通讯作者：
Woolford, Alison J. -A.
DOI：
10.1073/pnas.1424313112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Pabla, Navjotsingh;Gibson, Alice A.;Sparreboom, Alex
通讯作者：
Sparreboom, Alex